1.1 TECHNICAL FIELD
This invention relates to compositions comprising a colloidal or particulate metal oxide dissolved or suspended in a liquid carrier to which a soluble low molecular weight carbohydrate has been added. It has been discovered that the low molecular weight carbohydrate imparts significant stability to the compositions over a wide range of conditions without modifying the surface of the metal oxide. As such, the low molecular weight additives are useful in the formulation of diverse metal oxide products, including magnetic resonance contrast agents, anemia-treating pharmaceuticals and ferrofluids.
1.2 BACKGROUND ART
The advent of magnetic resonance imaging in medicine has led to the investigation of a wide range of materials as magnetic resonance (MR) contrast agents. Some of the materials investigated are colloidal or particulate in nature. When colloidal or particulate materials are used as parenteral MR contrast agents, the presence of large particles or aggregates can be life-threatening to the subject recipient. In addition, considerations of consumer convenience, and the economic desirability of manufacturing a small number of large lots, require both a long shelf life and the storage of the colloid/particulate materials at ambient temperatures. The development of commercial parenteral MR contrast agents based on colloidal and particulate active ingredients requires that the desirable physical properties of the colloid/particulate material be maintained over a wide range of conditions.
So-called lyophobic colloids and particulate solutions (colloids/particulates with water repelling surfaces) exhibit a general tendency to form high molecular weight aggregates or frank particles upon storage. An example of this phenomenon includes the observation of aggregate formation when superparamagnetic iron oxide is subjected to autoclaving conditions (see FIG. 5 of U.S. Pat. No. 4,827,945 incorporated above by reference). Addition of a polycarboxylate, such as citrate, prevents this undesirable aggregation. However, it is difficult to make the citrate-stabilized fluids isotonic. An advantage of the low molecular weight carbohydrate stabilizers of the current invention is that they can be used to adjust the osmotic pressure of the administered fluid over a wide range. In particular, they can be added to produce an isotonic fluid.
A common approach to the problem of instability in lyophobic colloids and particulate solutions involves the binding of certain agents to the surface of the colloid or particulate, so as to provide increased compatibility between the very large surface area of the colloid/particulate (i.e., large surface area per gram of colloid/particulate) and the solvent. This compatibility between surface and solvent leads to increased stability of the colloid/particulate upon autoclaving and/or storage. Polymeric, high molecular weight agents such as dextran (Hasegawa et al., U.S. Pat. No. 4,101,435; Molday, U.S. Pat. No. 4,452,773 both incorporated herein by reference), bovine serum albumin (Owen, U.S. Pat. No. 4,795,698 incorporated herein by reference) and organosilane (Whitehead, U.S. Pat. No. 4,695,392 incorporated herein by reference) have been used to coat (or otherwise associate with) and presumably to stabilize colloid/particulate solutions. Currently known polymeric stabilizing agents typically have molecular weights above about 5,000 daltons. However, one significant problem encountered in the association of polymers with the surface of the colloid or particulate is that the polymers frequently dissociate from the surface upon prolonged storage or under high temperatures. Such dissociation directly and significantly decreases the stability of the colloid/ particulate solutions.
Dextran/magnetite is an example of a particulate solution specifically noted to be stabilized by the polymeric dextran (see Hasegawa et al., U.S. Pat. No. 4,101,435, column 4, lines 9-43). Several workers have used dextrans of various molecular weights as ingredients in the synthesis of magnetic colloids or particles (see Hasegawa et al., U.S. Pat. No. 4,101,435; Molday, U.S. Pat. No. 4,454,773; Schroder U.S. Pat. No. 4,501,726 incorporated herein by reference). The resulting complexes of dextran and iron oxide have varying sizes and structures, but all have molecular weights of at least about 500,000 daltons. The incorporation of high molecular weight dextran into magnetic particles or colloids may, however, cause some patients to experience adverse reactions to the dextran, when such complexes are administered as parenteral MR contrast agents. These adverse reactions may also in part be due to the previously discussed problem of the high molecular weight polymers such as dextran which dissociate from the metal oxide colloid or particle upon prolonged storage or under high temperatures, leaving the metal oxide free to aggregate.
Similarly, a stable colloidal complex of ferric hydroxide and partially depolymerized dextran has been used in the treatment of iron-deficiency aneamia (Herb, U.S. Pat. No. 2,885,393; London, et al., U.S. Pat. No. 2,820,740 and U.S. Pat. No. Re. 24,642 all incorporated herein by reference). The most suitable range in molecular weight of the partially depolymerized dextran for injection was found to be 30,000 to 80,000 daltons or lower. (Herb, U.S. Pat. No. 2,885,393 col. 2 line 1-7).
Ferrofluids involve another example of the stabilization of magnetic colloids/particulates through surface modification. Typically, low molecular weight (less than 5,000 daltons) detergents are bound to the surface of a particulate solution of magnetic iron oxide (Rosensweig, R., Scientific American, October 1982, pp. 136-145; Khalafalla, U.S. Pat No. 4,208,294; Kovac U.S. Pat. No. 3,990,981, all incorporated herein by reference).
A final approach to the stabilization of colloids involves the addition of polymeric agents to the solvent. Such agents can adsorb to the surface of the colloid in a weak, reversible fashion, changing the surface characteristics sufficiently to enhance stability. There are several problems with adding free polymer as a stabilizing agent for colloids, and in particular for the stabilization of colloids or particles for parenteral administration (e.g., injection). First, upon storage the free polymer may aggregate, producing a liquid with unacceptable physical properties. This aggregation can occur when a polymeric stabilizer is employed that is capable of gelation or aggregation over the storage period. Polymers that have been used for stabilizing colloids that exhibit the property of gelation are gelatin and high molecular weight dextran. Second, after injection, adverse reactions to free polymer are possible. For example, injection of dextran as a plasma expander is associated with adverse reactions (Mishler, J. H., Clinics in Haemotology 13:75-92 (1984) incorporated herein by reference).